The renin-angiotensin system (RAS; also designated as renin-angiotensin aldosterone system, RAAS) is a key regulator of cardiovascular functions as well as for the balance of electrolytes and for maintaining body fluid volume, and a determinant of blood pressure (cf., for example, E. Lonn, Can. J. Cardiol. 20 (Suppl. B) (2004), 83B; I. A. Reid, Am. J. Physiol.: Advances in Physiology Education 20 (1998), S236). It acts via the effects of angiotensin II, an octapeptide hormone, which binds to angiotensin receptors. The formation of angiotensin II involves two main steps. In the first step, renin (EC 3.4.23.15; formerly EC 3.4.99.19 and EC 3.4.4.15), a 340 amino acid aspartyl proteinase, cleaves angiotensinogen to form the biologically inactive decapeptide angiotensin I. In the second step, angiotensin I is converted into angiotensin II by the zinc-dependent protease angiotensin-converting enzyme (ACE).
Renin is produced in the juxtaglomerular cells of the kidney primarily in the form of the biologically inactive prorenin. Its release from the kidney and activation and subsequent RAS activation in normotensive humans is stimulated by sodium or volume depletion, or by a reduction in blood pressure.
RAS activity is the principal determinant of several pathological states since angiotensin II, the major effector molecule of this system, increases blood pressure both directly by arterial vasoconstriction and indirectly by liberating the sodium-retaining hormone aldosterone from the adrenal glands, accompanied by an increase in extracellular fluid volume, as well as having growth-promoting effects on vascular, cardiac and renal tissues which contribute to end-organ damage.
Pharmacological blockade of the RAS is an established way of treating various diseases, for example hypertension (cf., for example, Handbook of Hypertension, W. H. Birkenhäger et al. (ed.), Elsevier Science Publishers, Amsterdam (1986), vol. 8, 489). However, the therapeutic response achieved with the currently used types of RAS blockers, ACE inhibitors and angiotensin receptor blockers, although efficacious, is limited. This may be due to the rise in renin which is induced by these agents and results in an increase in angiotensin I which can be converted into angiotensin II via other pathways than by means of ACE. An inhibition of renin, which controls the initial and rate-limiting step in the RAS by catalyzing the cleavage of the Leu10-Val11 peptide bond of angiotensinogen resulting in the formation of the angiotensin peptides, would inhibit the complete RAS and thus be more efficient. Furthermore, whereas inhibition of ACE also affects the level of other peptides which are cleaved by ACE such as bradykinin, for example, which is associated with side effects of ACE inhibitors like cough or angioedema, renin is specific in that angiotensinogen is its only natural substrate. Inhibition of renin thus offers a specific and powerful way of lowering blood pressure (cf. M. Moser et al., J. Clin. Hypertension, 9 (2007), 701) as well as providing organ protection of organs such as the heart, kidney and brain and, besides for treating hypertension, thus is useful for treating disorders of the cardiovascular system, such as heart failure, cardiac insufficiency, cardiac failure, cardiac infarction, cardiac hypertrophy, vascular hypertrophy, left ventricular dysfunction, in particular left ventricular dysfunction after myocardial infarction, restenosis and angina pectoris; renal diseases, such as renal fibrosis, renal failure and kidney insufficiency; diabetes complications, such as nephropathy and retinopathy; glaucoma; and cerebral afflictions, such as cerebral hemorrhage, for example (with respect to the effect of the RAS on renal diseases and cardiac damage, cf., for example, U. C. Brewster, Am. J. Med. 116 (2004), 263; J. Gaedeke et al., Expert Opin. Pharmacother. 7 (2006), 377; B. Pilz et al., Hypertension 46 (2005), 569).
A large number of peptidic and peptidomimetic inhibitors of human renin with various stable transition-state analogues of the scissile peptide bond have been developed since about 1980 and contributed to the validation of renin as a therapeutic target (cf., for example, B. B. Scott et al., Curr. Protein Pept. Sci. 7 (2006), 241; J. Maibaum et al., Expert Opin. Ther. Patents 13 (2003), 589). However, these compounds generally suffer from deficiencies such as insufficient bioavailability (cf. H. D. Kleinert, Cardiovasc. Drugs Therapy 9 (1985), 645) or duration of action, or high cost of production. Recently, an orally active renin inhibitor, aliskiren (cf. Drugs Fut. 26 (2001), 1139; J. Wood et al., J. Hypertens. 23 (2005), 417; M. Azizi et al., J. Hypertens. 24 (2006), 243) has been marketed. But the property profile of aliskiren is not yet ideal, for example with respect to oral bioavailability, and a particular drawback of aliskiren is its complex molecular structure with four chiral centers and its multistep synthesis. Thus, there is still a great need for new, non-peptidic small molecule renin inhibitors which exhibit favorable properties, for example with respect to oral bioavailability or low molecular complexity and simple synthetic access. The present invention satisfies this need by providing the renin-inhibiting cyclic indole-3-carboxamides of the formula I.
Various indole derivatives have already been described. For example, in US 2005/0054631 and U.S. Pat. No. 4,148,895 certain indole derivatives are described which comprise an amino group in the 2-position of the indole ring and which are inhibitors of poly(adenosine 5′-diphosphate ribose)polymerase (PARP) useful for the treatment of a variety of diseases including diseases associated with the central nervous system and cardiovascular disorders, or exhibit hypotensive and especially antiarrhythmic activity, respectively. In EP 1452525 indole derivatives are described which, among others, can contain in the 3-position of the indole ring a carboxamide group wherein the amide nitrogen atom is a ring member of a diazacycloalkane which carries on the second ring nitrogen atom a pyridine, pyrazine, pyridazine or pyrimidine group, and which are inhibitors of transforming growth factor β (TGF-β) useful for the treatment of fibroproliferative disorders, for example. Similar indole-3-carboxamide derivatives which are inhibitors of TGF-β and are useful for the treatment of fibroproliferative disorders or specifically for the treatment of nephritis, are described in EP 1156045 and EP 1243268. WO 2005/121175 relates to CD4 mimetic compounds, among them indole derivatives which can contain a carboxamide group the amide nitrogen atom of which is a member of a ring, which complex with envelope proteins of human immunodeficiency virus and are useful for eliciting an immune response. WO 99/43672, WO 99/43654 and U.S. Pat. No. 6,500,853 relate in a very broad manner to derivatives of indole, indoline and other heterocycles, among them indolecarboxamides, which are phospholipase A2 inhibitors and are useful for the treatment of inflammatory conditions. The indole-3-carboxamides of the present invention, wherein the amide nitrogen atom is a ring member of a 1,4- or 1,5-diazacycloalkane ring system, the nitrogen atom in position 1 of the indole ring system carries a cyclic group, and the carbon atom in position 2 of the indole ring system is linked to a (hetero)aromatic group, have not yet been disclosed.